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. 1993 Jul;36(4):251–259. doi: 10.1007/BF01740907

Cellular and cytokine responses of the human central nervous system to intracranial administration of tumor necrosis factor α for the treatment of malignant gliomas

Mitsuhiro Tada 1,✉, Yutaka Sawamura 1, Shirou Sakuma 1, Kazuo Suzuki 2, Hidemi Ohta 3, Toshimitsu Aida 1, Hiroshi Abe 1
PMCID: PMC11039008  PMID: 7679950

Abstract

To elucidate the role of tumor necrosis factor α (TNFα) as a biological response modifier, we studied cellular and cytokine responses of the central nervous system to TNFα administered intracranially in a phase I clinical trial for patients with malignant gliomas. Six patients received injections of TNFα (1.25×103−10×103 U/injection) into the tumor cavities, and regional fluids (RF) and lumbar cerebrospinal fluids (CF) were serially sampled before and after the injections. Recruitment of neutrophils occurred, mostly peaking 8 h after TNFα injection, and fewer numbers of CD4+ T cells and monocytes/macrophages migrated, subsequently peaking at 24 h. The CF leukocytosis persisted for 48 h and was associated with an increased level of neutrophil chemotactic activity in the CF. This neutrophil chemotactic activity was attributed to interleukin-8 (IL-8) by HPLC. The level of IL-6 activity in the CF and RF consistently increased; beginning 2 h after TNFα injection and reaching the maximum between 8 h and 12 h. It returned to the basal level within 48 h. IL-1β was detected in the CF of three patients, its level peaking at 8 h. Prostaglandin E2 also increased after injection of TNFα, peaking between 4 h and 12 h and then gradually decreasing. Transforming growth factor γ was found in all cases tested and one patient showed a significant change after TNFα injection. IL-2 activity, interferon α (INFα) activity, IFNβ, and granulocyte/macrophage-colony-stimulating factor were not detected in the CF or RF. In conclusion, TNFα is biologically effective in inducing migration of immune cells and generating multiple cytokine responses in the human central nervous system.

Key words: Tumor necrosis factor α, Intracranial injection, Malignant glioma, Leukocyte recruitment, Cytokine response

References

  • 1.Abe Y, Sekiya S, Yamashita T, Sendo F. Vascular hyperpermeability induced by tumor necrosis factor and its augmentation by IL-1 and IFN-γ is inhibited by selective depletion of neutrophils with a monoclonal antibody. J Immunol. 1990;145:2902–2902. [PubMed] [Google Scholar]
  • 2.Bartsch HH, Pfizenmaier K, Schröder M, Nagel GA. Intralesional application of recombinant human tumor necrosis factor α induces local tumor regression in patients with advanced malignancies. Eur J Cancer Clin Oncol. 1989;25:287–287. doi: 10.1016/0277-5379(89)90021-7. [DOI] [PubMed] [Google Scholar]
  • 3.Berendt MJ, Morth RJ, Kirstein DP. The immunological basis of endotoxin-induced tumor regression. Requirement for a preexisting state of concomitant anti-tumor immunity. J Exp Med. 1978;148:1560–1560. doi: 10.1084/jem.148.6.1560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Black KL, Hoff JT, McGillicuddy JE, Gebarski SS. Increased leukotriene C4 and vasogenic edema surrounding brain tumors in humans. Ann Neurol. 1986;19:592–592. doi: 10.1002/ana.410190613. [DOI] [PubMed] [Google Scholar]
  • 5.Blick M, Sherwin SA, Rosenblum M, Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res. 1987;47:2986–2986. [PubMed] [Google Scholar]
  • 6.Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA. 1975;72:3666–3666. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Conkling PR, Chua CC, Nadler P, Greenberg CS, Doty E, Misukonis MA, Haney AF, Bast RC, Jr, Weinberg JB. Clinical trials with human tumor necrosis factor: in vivo and in vitro effects on human mononuclear phagocyte function. Cancer Res. 1988;48:5604–5604. [PubMed] [Google Scholar]
  • 8.Creagan ET, Kovach JS, Moetel CG, Frytak S, Kvols LK. A phase I clinical trial of recombinant human tumor necrosis factor. Cancer. 1988;62:2467–2467. doi: 10.1002/1097-0142(19881215)62:12<2467::aid-cncr2820621202>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  • 9.Creaven PJ, Brenner DE, Cowens JW, Huben RP, Wolf RM, Takita H, Arbuck SG, Razack MS, Proefrock AD. A phase I clinical trial of recombinant human tumor necrosis factor given daily for five days. Cancer Chemother Pharmacol. 1989;23:186–186. doi: 10.1007/BF00267953. [DOI] [PubMed] [Google Scholar]
  • 10.Dinarello CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B, Cerami A, Figari IS, Palladino MA, Jr, O'Connor JV. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986;163:1433–1433. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Dinarello CA, Cannon JG, Mier JW, Bernheim HA, LoPreste G, Lynn DL, Love RN, Webb AC, Auron PE, Reuben RC, Rich A, Wolff S, Putney SD. Multiple biological activities of human recombinant interleukin 1. J Clin Invest. 1986;77:1734–1734. doi: 10.1172/JCI112495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Elias JA, Lentz V. IL-1 and tumor necrosis factor synergistically stimulate fibroblast IL-6 production and stabilize IL-6 messenger RNA. J Immunol. 1990;145:161–161. [PubMed] [Google Scholar]
  • 13.Feinberg B, Kurzrock R, Talpaz M, Blick M, Saks S, Gutterman JU. A phase I clinical trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients. J Clin Oncol. 1988;6:1328–1328. doi: 10.1200/JCO.1988.6.8.1328. [DOI] [PubMed] [Google Scholar]
  • 14.Flick DA, Figgord GE. Comparison of in vitro cell cytotoxic assay for tumor necrosis factor. J Immunol Methods. 1984;68:167–167. doi: 10.1016/0022-1759(84)90147-9. [DOI] [PubMed] [Google Scholar]
  • 15.Frei K, Malipiero UV, Leist TP, Zinkernagel RM, Schwab ME, Fontana A. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Immunol. 1989;19:689–689. doi: 10.1002/eji.1830190418. [DOI] [PubMed] [Google Scholar]
  • 16.Grunfeld C, Palladino MA., Jr Tumor necrosis factor: immunologic, antitumor, metabolic, and cardiovascular activities. Adv Intern Med. 1990;35:45–45. [PubMed] [Google Scholar]
  • 17.Gamble JR, Harlan JM, Klebanoff SJ, Vadas MA. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci USA. 1985;82:8667–8667. doi: 10.1073/pnas.82.24.8667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Helseth E, Torp S, Dalen A, Unsgaard G. Effects of interferon-gamma and tumor necrosis factor-alpha on clonogenic growth of cell lines and primary cultures from human gliomas and brain metastases. APMIS. 1989;97:569–569. doi: 10.1111/j.1699-0463.1989.tb00832.x. [DOI] [PubMed] [Google Scholar]
  • 19.Jablons DM, Mule JJ, McIntosh JK, Sehgal PB, May LT, Huang CM, Rosenberg SA, Lotze MT. IL-6/IFN-β as a circulating hormone: induction by cytokine administration in humans. J Immunol. 1989;142:1542–1542. [PubMed] [Google Scholar]
  • 20.Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, Kishimoto T. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988;332:83–83. doi: 10.1038/332083a0. [DOI] [PubMed] [Google Scholar]
  • 21.Lachman L, Brown DC, Dinarello CA. Growth-promoting effect of recombinant interleukin 1 and tumor necrosis factor for a human astrocytoma cell line. J Immunol. 1987;138:2913–2913. [PubMed] [Google Scholar]
  • 22.Larsen CG, Anderson AO, Appella E, Oppenheim JJ, Matsushima K. The neutrophil-activating protein (NAP-1) is also chemotactic for T lymphocytes. Science. 1989;243:1464–1464. doi: 10.1126/science.2648569. [DOI] [PubMed] [Google Scholar]
  • 23.Leist TP, Frei K, Kam-hansen S, Zenkernagel RM, Fontana A. Tumor necrosis factor alpha in cerebrospinal fluid during bacterial but not viral meningitis. J Exp Med. 1988;167:1743–1743. doi: 10.1084/jem.167.5.1743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.LeMay LG, Vander AJ, Kuluger MJ. Role of interleukin 6 in fever in rats. Amer J Physiol. 1990;258:R798–R798. doi: 10.1152/ajpregu.1990.258.3.R798. [DOI] [PubMed] [Google Scholar]
  • 25.Midorikawa Y, Yamashita T, Sendou F. Modulation of the immune response to transplanted tumors in rats by selective depletion of neutrophils in vivo using a monoclonal antibody: abrogation of specific transplantation resistance to chemical carcinogen-induced syngenic tumors by selective depletion of neutrophils in vivo. Cancer Res. 1990;50:6243–6243. [PubMed] [Google Scholar]
  • 26.Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–55. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  • 27.Mrowietz U, Schröder J-M, Christophers E. Recombinant human tumor necrosis factor α lacks chemotactic activity for human peripheral blood neutrophils and monocytes. Biochem Biophys Res Commun. 1988;153:1223–1223. doi: 10.1016/s0006-291x(88)81358-5. [DOI] [PubMed] [Google Scholar]
  • 28.Mulé JJ, McIntosh JK, Jablons DM, Rosenberg SA. Antitumor activity of recombinant interleukin 6 in mice. J Exp Med. 1990;171:629–629. doi: 10.1084/jem.171.3.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Mustafa MM, Ramilo O, Sáez-Llorens X, Olsen KD, Magness RR, McCracken GH., Jr Cerebrospinal fluid prostaglandins, interleukin 1β, and tumor necrosis factor in bacterial meningitis. Am J Dis Child. 1990;144:883–883. doi: 10.1001/archpedi.1990.02150320047024. [DOI] [PubMed] [Google Scholar]
  • 30.Nobuhara M, Kanamori T, Ashida Y, Ogino H, Horisawa Y, Nakayama K, Asami T, Iketani M, Noda K, Andoh S, Kurimoto M. The inhibition of neoplastic cell proliferation with human natural tumor necrosis factor. Jpn J Cancer Res. 1987;78:193–193. [PubMed] [Google Scholar]
  • 31.North RJ, Bursuker I. Generation and decay of the immune response to a progressive fibrosarcoma. J Exp Med. 1984;159:1295–1295. doi: 10.1084/jem.159.5.1295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Otsuka Y, Nagano K, Nagano K, Hori K, Oh-ishi J, Hayashi H, Watanabe N, Niitsu Y. Inhibition of neutrophil migration by tumor necrosis factor. Ex vivo and in vivo studies in comparison with in vitro effect. J Immunol. 1990;145:2639–2639. [PubMed] [Google Scholar]
  • 33.Pfreundschuh MG, Steinmetz HT, Tüschen R, Schenk V, Diehl V, Schaadt M. Phase I study of intratumoral application of recombinant human tumor necrosis factor. Eur J Cancer. 1988;25:379–379. doi: 10.1016/0277-5379(89)90034-5. [DOI] [PubMed] [Google Scholar]
  • 34.Platanias LC, Vogelzang NJ. Interleukin-1: biology, pathophysiology, and clinical prospects. Am J Med. 1990;89:621–621. doi: 10.1016/0002-9343(90)90181-c. [DOI] [PubMed] [Google Scholar]
  • 35.Ramilo I., Sáez-Llorens X, Mertsola J, Jafari H, Olsen KD, Hansen EJ, Yoshinaga M, Ohkawara S, Nariuchi H, McCracken GH., Jr Tumor necrosis factor alpha/cachectin and interleukin 1 beta initiate meningeal inflammation. J Exp Med. 1990;172:497–497. doi: 10.1084/jem.172.2.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Robinson EA, Yoshimura T, Leonard EJ, Tanaka S, Griffin PR, Shabanowitz J, Hunt DF, Appella E. Complete amino acid sequence of a human monocyte chemoattractant, a putative mediator of cellular immune reactions. Proc Natl Acad Sci USA. 1989;86:1850–1850. doi: 10.1073/pnas.86.6.1850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ruggiero V, Latham K, Baglioni C. Cytostatic and cytotoxic activity of tumor necrosis factor on human cancer cells. J Immunol. 1987;138:2711–2711. [PubMed] [Google Scholar]
  • 38.Rutka JT, Giblin JR, Berens ME, Bar-Shiva E, Tokuda K, McCulloch JR, Rosenblum ML, Eessalu TE, Aggarwal BB, Bodell WJ. The effects of human recombinant tumor necrosis factor on glioma-derived cell lines: cellular proliferation, cytotoxicity, morphological and radioreceptor studies. Int J Cancer. 1988;41:573–573. doi: 10.1002/ijc.2910410417. [DOI] [PubMed] [Google Scholar]
  • 39.Saukkonen K, Sande S, Gioffe C, Wolpe S, Sherry B, Cerami A, Tuomanen E. The role of cytokines in the generation of inflammation and tissue damage in experimental gram-positive meningitis. J Exp Med. 1990;171:439–439. doi: 10.1084/jem.171.2.439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Sawamura Y, de Tribolet N. advances and technical standards in neurosurgery, vol 17. Wien, New York: Springer; 1990. Immunobiology of brain tumors; pp. 3–3. [DOI] [PubMed] [Google Scholar]
  • 41.Sawamura Y, Diserens A-C, de Tribolet N. In vitro prostaglandin E2 production by glioblastoma cells and its effect on interleukin-2 activation of oncolytic lymphocytes. J Neurooncol. 1990;9:125–125. doi: 10.1007/BF02427832. [DOI] [PubMed] [Google Scholar]
  • 42.Schall TJ, Bacon K, Toy KJ, Goeddel DV. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature. 1990;347:669–669. doi: 10.1038/347669a0. [DOI] [PubMed] [Google Scholar]
  • 43.Schell-Frederick E, Tepass T, Lorscheidt G, Pfreundschuh M, Schaadt M, Diehl V. Effects of recombinant tumor necrosis factor (rHuTNFα) on human neutrophils and monocytes: in vitro, ex vivo and in vivo. Eur J Haematol. 1989;43:286–286. doi: 10.1111/j.1600-0609.1989.tb00301.x. [DOI] [PubMed] [Google Scholar]
  • 44.Schiller JH, Storer BE, Witt PL, Alberti D, Tombes MB, Arzoomanian R, Procter RA, McCarthy D, Brown RR, Voss SD, Remick SC, Grem JL, Borden EC, Trump DL. Biological and clinical effects of intravenous tumor necrosis factor-α administered three times weekly. Cancer Res. 1991;51:1651–1651. [PubMed] [Google Scholar]
  • 45.Schleuning M, Munker R. Tumor necrosis factor: an update on basic research and clinical applications. Klin Wochenschr. 1990;68:841–841. doi: 10.1007/BF01662779. [DOI] [PubMed] [Google Scholar]
  • 46.Selby P, Hobbs S, Viner C, Jackson E, Jones A, Newell D, Calvert AH, McElwain T, Fearon K, Humphereys J, Shiga T. Tumour necrosis factor in man: clinical and biological observations. Br J Cancer. 1987;56:803–803. doi: 10.1038/bjc.1987.294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Sherman ML, Spriggs DR, Arthur KA, Imamura K, Frei E, III, Kufe DW. Recombinant human tumor necrosis factor administered as five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism. J Clin Oncol. 1988;6:344–344. doi: 10.1200/JCO.1988.6.2.344. [DOI] [PubMed] [Google Scholar]
  • 48.Spriggs DR, Sherman ML, Michie H, Arthur KA, Imamura K, Wilmore D, Frei E, III, Kufe DW. Recombinant human tumor necrosis factor administered as 24-h intravenous infusion. A phase I and pharmacologic study. JNCI. 1988;80:1039–1039. doi: 10.1093/jnci/80.13.1039. [DOI] [PubMed] [Google Scholar]
  • 49.Strieter RM, Kunkel SL, Showell HJ, Remick DG, Phan SH, Ward PA, Marks RM. Endothelial cell gene expression of a neutrophil chemotactic factor by TNFα, LPS, and IL-1β. Science. 1989;243:1467–1467. doi: 10.1126/science.2648570. [DOI] [PubMed] [Google Scholar]
  • 50.Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA, Jr, Shepard HM. Recombinant human tumor necrosis factor-α: Effects on proliferation of normal and transformed cells in vitro. Science. 1985;22:943–943. doi: 10.1126/science.3933111. [DOI] [PubMed] [Google Scholar]
  • 51.Suzuki K, Asaoka K, Takahashi K, Fujikura T. Differences among primates in defence against infection: sensitivity of polymorphonuclear leukocytes to fMet-Leu-Phe. Cell Biochem Funct. 1985;3:297–297. doi: 10.1002/cbf.290030409. [DOI] [PubMed] [Google Scholar]
  • 52.Suzuki K, Miyasaka H, Ota H, Yamakawa Y, Tagawa M, Kuramoto A, Mizuno S. Purification and partial primary sequence of a chemotactic protein for polymorphonuclear leukocyte derived from human lung giant cell carcinoma LU65C cells. J Exp Med. 1989;169:1895–1895. doi: 10.1084/jem.169.6.1895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Van Meir E, Sawamura Y, Diserens A-C, Hamou M-F, de Tribolet N. Human glioblastoma cells release interleukin 6 in vivo and in vitro. Cancer Res. 1990;50:6683–6683. [PubMed] [Google Scholar]
  • 54.Van Meir E, Ceska M, Effenberger F, Walz A, Grouzmann E, Desbaillets I, Frei K, Fontana A, de Tribolet N. Interleukin-8 is produced in neoplastic and infectious diseases of the human central nervous system. Cancer Res. 1992;52:4297–4297. [PubMed] [Google Scholar]
  • 55.Waage A, Halstensen A, Shalaby R, Brandtzaeg P, Kierulf P, Espevik T. Local production of tumor necrosis factor alpha, interleukin 1, and interleukin 6, in meningococcal meningitis. Relation to the inflammatory response. J Exp Med. 1989;170:1859–1859. doi: 10.1084/jem.170.6.1859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Wrann M, Bodmer S, de Martin R, Siepl C, Hofer-Warbinek R, Frei K, Hofer E, Fontana A. T cell suppressor factor from human glioblastoma cells is a 12.5-kd protein closely related to transforming growth factor-β. EMBO J. 1987;6:1633–1633. doi: 10.1002/j.1460-2075.1987.tb02411.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Zuber P, Accolla RS, Carrel S, Diserens AC, de Tribolet N. Effects of recombinant human tumor necrosis factor-α on the surface phenotype and the growth of human malignant glioma cell lines. Int J Cancer. 1988;42:780–780. doi: 10.1002/ijc.2910420525. [DOI] [PubMed] [Google Scholar]

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